Differences in the nitrite ion formation and the toxicological findings between isosorbide dinitrate and isosorbide-5-mononitrate

Abstract

In the metabolism of isosorbide dinitrate (ISDN), fast denitration with the formation of nitrite ions and a mononitrate plays an important role. In contrast, the denitration of isosorbide-5-mononitrate (IS-5-MN) to isosorbide is very slow. Accordingly po administration of high doses of ISDN (92.5 and 236 mg/kg) in conscious dogs led to maximum nitrite concentrations in the blood of 0.9 and 3.3 mg/liter, respectively. In contrast, with equimolar doses of IS-5-MN (75 and 191 mg/kg) we were able to detect nitrite ions reliably only at the higher dose and this gave a maximum blood concentration of 0.4 mg/liter. The rise in nitrite ion concentration is followed by the formation of methemoglobin. As is known from the literature, there is a rise in the activity of alkaline phosphatase in the serum of rabbits in addition to methemoglobin formation following repeated administration of sodium nitrite. So we have specifically investigated whether this is also the case following ISDN and IS-5-MN administration. On po administration of 236 mg/kg ISDN/day to dogs, there was a continuous rise in alkaline phosphatase from about the 20th day onward which we did not observe after the equimolar dose of IS-5-MN (191 mg/kg). NaNO2, 35 mg/kg po, led to a comparable maximal rise in methemoglobin to that obtained with 236 mg/kg ISDN. Repeated po administration of 35 mg/kg NaNO2/day also caused a rise in alkaline phosphatase. It is concluded that the formation of nitrite ions from ISDN is the reason for the rise in methemoglobin and alkaline phosphatase. The lower formation of nitrite ions from IS-5-MN can also be of clinical importance, at least in certain cases.